Among our best tools for the control of malaria are effective antimalarial drugs and insecticides, but these are jeopardized by increasing resistance of malaria parasites and anopheline mosquitoes. Parasite and mosquito resistance are partially characterized, and assays are available to identify certain genotypes associated with resistance. However, additional studies to identify novel markers of resistance, especially to newer drugs and insecticides, are needed. This project will utilize available tools to conduct efficient surveys of the prevalence of known resistance markers across Uganda, develop new tools to improve surveillance methods, search for new markers to allow us to track the development of resistance to newer drugs and insecticides, and identify associations between specific intervenfions and the development of resistance. We hypothesize that benefits of current malaria control measures will be challenged by increasing resistance in malaria parasites and anopheline vectors. We further hypothesize that the rate of resistance development will vary depending on the level of malaria transmission and extent of implementation of control measures. We will test these hypotheses with serial surveys for parasite and mosquito resistance mediators at sites with varied malaria transmission intensity. We also predict that newer agents will select for not-yet-described resistance mediators. We will search for these novel mediators of resistance in samples under drug and insecticide selection pressure. Our specific aims will be: 1) to compare the prevalence of molecular markers of antimalarial drug resistance by serial surveillance at diverse sites in Uganda with varied implementation of control measures, 2) to compare the prevalence of molecular markers of anopheline insecticide resistance by serial surveillance at diverse sites in Uganda with varied implementation of control measures, and 3) to improve surveillance tools and search for novel mediators of antimalarial and insecticide resistance using transcriptome and high throughput sequencing techniques. We anficlpate that this project will offer a detailed characterization of the progression of resistance to drugs and insecticides in Uganda over time and also help us to identify novel mechanisms of resistance.